Delivery of drugs by the transdermal route has been known to be theoretically possible for many years. The earliest patented transdermal devices were medicated bandages, usually with the drug mixed into the adhesive, that were designed to bring a known quantity of drug to a known area of skin for a known time. Such devices usually did not control the rate at which the drug was released. Since the 1970's interest in using the transdermal route for controlled release therapy has grown substantially, as evidenced by the large number of U.S. Patents in the area now. Controlled release transdermal devices rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, generally a day, several days, or a week. Two mechanisms are used to regulate the drug flux: either the drug is contained within a drug reservoir, which is separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, and through which the drug diffuses to the skin. Devices incorporating a reservoir will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug. To date limited commercial exploitation of this technology has been achieved, because of the many practical problems to be overcome with real devices. The skin is an effective barrier against the majority of drugs. Unless the delivery device is made unacceptably large, or the natural skin permeation rate of the drug is somehow increased by the use of enhancers, then the drug flux across the skin is inadequate for useful therapy. Thus although in theory any drug might be delivered by this route, serious investigation of candidate drugs has been limited to those few that exhibit suitable properties, namely: small molecular size; short half-life; they are metabolized rapidly by the liver, and thus difficult to administer orally; high in vivo skin permeability; and small effective therapeutic dose. Despite active work in the field since at least 1970, at present commercial patches are available for delivery of only four drugs: nitroglycerin, scopolamine, clonidine, and estradiol.
The U.S. Surgeon General has determined that cigarette smoking is a major risk factor in coronary heart disease and is the cause of approximately 30% of all cancer deaths. However, it is very difficult to give up smoking, and any smoking cessation therapy has to deal with both the pharmacological and the psychological dependence on cigarettes. Separating the treatment of these two factors is an approach that has been tried with modest success, for example by satisfying the pharmacological craving with nicotine pills or chewing gum, while treating the psychological dependence. The difficulty with oral administration is that it leads to irregular and unpredictable blood plasma levels. To date, the best results have been obtained with nicotine chewing gum, which achieves direct delivery to the systemic circulation by buccal absorption. However, chewing gum formulations taste bad, may lead to mouth ulcers and heartburn, cannot be used effectively by denture wearers, and dosage control depends too much on patient compliance.
The concept of applying the teachings of transdermal drug therapy to the delivery of nicotine, which is not a therapeutic drug, is described in U.S. Pat. No. 4,597,961. This patent discloses a transdermal patch comprising an occlusive backing, a nicotine reservoir containing liquid nicotine, either alone or with a carrier or solvent, and a microporous membrane. Nicotine is highly lipid soluble, so no enhancement of the skin permeation rate is necessary to achieve a blood plasma level comparable with that obtained from smoking. Nicotine is highly toxic, and the addition of oils or gels that may dilute the nicotine in the reservoir, and hence slow the flux through the microporous membrane, is suggested in the above patent. All the controlled release embodiments described in the patent, however, employ a microporous membrane, and there is no suggestion that it would be possible to control the delivery of nicotine at a dose that is large enough to satisfy or alleviate the physiological craving, but that is below the toxic threshold, in some other way. The duration of nicotine delivery from the patch disclosed in U.S. Pat. No. 4,597,961 is of the order 30-45 minutes. To maintain nicotine plasma levels sufficiently high to alleviate the craving for cigarettes, the application of many patches per day would then be necessary.
The present invention is directed to the discovery that in spite of nicotine being very volatile and highly toxic, it is possible to make a simple monolithic device that can contain and release nicotine at useful, yet non-toxic levels, for periods of 24 hours or more.